Hereditary gingival fibromatosis associated with the missense mutation of the KCNK4 gene

Mariani, Pierluigi; Zhurakivska, Khrystyna; Santoro, Raffaela; Laino, G; Russo, Diana; Laino, Luigi

doi:10.1016/j.oooo.2020.08.006

Cited by 6 publications

(8 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, both Piezo1 and TREK/TRAAK MSCs appear to be important players in the mechanobiology of wound healing. Of note, rare inherited gain-offunction mutations in KCNK4 (hTRAAK) are associated with gingival fibromatosis in children (Bauer et al, 2018;Mariani et al, 2021). However, mouse gingival tissue lacks TRAAK but instead express TREK-1/2, further indicating important species differences in the expression of K 2P channels (Figure S7E).…”

Section: Discussionmentioning

confidence: 99%

Piezo1 and Piezo2 foster mechanical gating of K2P channels

et al. 2021

View full text Add to dashboard Cite

Mechanoelectrical transduction is mediated by the opening of different types of force-sensitive ion channels, including Piezo1/2 and the TREK/TRAAK K 2P channels. Piezo1 curves the membrane locally into an inverted dome that reversibly flattens in response to force application. Moreover, Piezo1 forms numerous preferential interactions with various membrane lipids, including cholesterol. Whether this structural architecture influences the functionality of neighboring membrane proteins is unknown. Here, we show that Piezo1/2 increase TREK/TRAAK current amplitude, slow down activation/deactivation, and remove inactivation upon mechanical stimulation. These findings are consistent with a mechanism whereby Piezo1/2 cause a local depletion of membrane cholesterol associated with a prestress of TREK/TRAAK channels. This regulation occurs in mouse fibroblasts between endogenous Piezo1 and TREK-1/2, both channel types acting in concert to delay wound healing. In conclusion, we demonstrate a community effect between different structural and functional classes of mechanosensitive ion channels.

show abstract

Section: Discussionmentioning

confidence: 99%

Piezo1 and Piezo2 foster mechanical gating of K2P channels

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Previously, two KCNK4 mutations were reported to be associated with the FHEIG syndrome ( Bauer et al, 2018 ; Mariani et al, 2021 ). Clinically, the FHEIG syndrome included not only neurological symptoms (epilepsy, development delays, and intellectual disability) but also non-neurological symptoms (facial dysmorphism, hypertrichosis, and gingival overgrowth) ( Bauer et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…The K2P4.1 channel, mainly distributed in the membrane of neurons, plays an essential role in controlling the resting membrane potential and regulating cellular excitability ( Brohawn et al, 2012 ). Previously, only two KCNK4 variants were identified to be associated with human disease ( Bauer et al, 2018 ; Mariani et al, 2021 ). The association between KCNK4 and human disease remains to be further researched with more cases.…”

Section: Introductionmentioning

confidence: 99%

Expanding the phenotypic spectrum of KCNK4: From syndromic neurodevelopmental disorder to rolandic epilepsy

Yan

Jin

Guo

et al. 2023

Front. Mol. Neurosci.

View full text Add to dashboard Cite

The KCNK4 gene, predominantly distributed in neurons, plays an essential role in controlling the resting membrane potential and regulating cellular excitability. Previously, only two variants were identified to be associated with human disease, facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth (FHEIG) syndrome. In this study, we performed trio-based whole exon sequencing (WES) in a cohort of patients with epilepsy. Two de novo likely pathogenic variants were identified in two unrelated cases with heterogeneous phenotypes, including one with Rolandic epilepsy and one with the FHEIG syndrome. The two variants were predicted to be damaged by the majority of in silico algorithms. These variants showed no allele frequencies in controls and presented statistically higher frequencies in the case cohort than that in controls. The FHEIG syndrome-related variants were all located in the region with vital functions in stabilizing the conductive conformation, while the Rolandic epilepsy-related variant was distributed in the area with less impact on the conductive conformation. This study expanded the genetic and phenotypic spectrum of KCNK4. Phenotypic variations of KCNK4 are potentially associated with the molecular sub-regional effects. Carbamazepine/oxcarbazepine and valproate may be effective antiepileptic drugs for patients with KCNK4 variants.

show abstract

“…TRAAK channels are expressed in periodontal ligament fibroblasts, KCNK4 mutations promote faster cell progression of gingival fibroblasts resulting in diffused gingival enlargement (Mariani et al, 2021; Urrego et al, 2014). In Patient 1, gingival fibromatosis prevented the proper eruption of teeth, which could be related to activation of K2P channels that may have subsequent effect on the mechanical stretch (Mariani et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Abnormal activation or inhibition of potassium (K+) currents across the cellular plasma membrane can alter the neurotransmission leading to endocrine and renal dysfunction, cardiac arrhythmias, and in some instances disrupted developmental processes (Bauer et al, 2018). The human KCNK4 is widely expressed in the brain, placenta, testis, small intestine, prostate, kidney, and periodontal ligament fibroblasts (Lesage et al, 2000; Mariani et al, 2021; Urrego et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

A recurrent KCNK4 variant in a dominant pedigree with hypertrichosis and gingival fibromatosis syndrome: Variable phenotypic expressivity and insights on patients' dental management

Elhossini,

Sayed,

Hellal

et al. 2023

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Abnormal hyperpolarization of the KCNK4 gene, expressed in the nervous system, brain, and periodontal ligament fibroblasts, leads to impaired neurotransmitter sensitivity, cardiac arrhythmias, and endocrine dysfunction, as well as, progressive cell proliferation. De novo gain of function variants in the KCNK4 gene were reported to cause a recognizable syndrome characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth (FHEIG, OMIM# 618381). FHEIG is extremely rare with only three reported cases in the literature. Herein, we describe the first inherited KCNK4 variant (c.730G>C, p.Ala244Pro) in an Egyptian boy and his mother. Variable phenotypic expressivity was noted as the patient presented with the full‐blown picture of the syndrome while the mother presented only with hypertrichosis and gingival overgrowth without any neurological manifestations. The c.730G>C (p.Ala244Pro) variant was described before in a single patient and when comparing the phenotype with our patient, a phenotype–genotype correlation seems likely. Atrial fibrillation and joint laxity are new associated findings noted in our patient extending the clinical phenotype of the syndrome. Dental management was offered to the affected boy and a dramatic improvement was noted as the patient regained his smile, restored the mastication function, and resumed his psychological stability.

show abstract

Hereditary gingival fibromatosis associated with the missense mutation of the KCNK4 gene

Cited by 6 publications

References 53 publications

Piezo1 and Piezo2 foster mechanical gating of K2P channels

Piezo1 and Piezo2 foster mechanical gating of K2P channels

Expanding the phenotypic spectrum of KCNK4: From syndromic neurodevelopmental disorder to rolandic epilepsy

A recurrent KCNK4 variant in a dominant pedigree with hypertrichosis and gingival fibromatosis syndrome: Variable phenotypic expressivity and insights on patients' dental management

Contact Info

Product

Resources

About